ABSTRACT
We describe the properties of a novel nonpeptide kinin B1 receptor antagonist, NVP-SAA164, and demonstrate its in vivo activity in models of inflammatory pain in transgenic mice expressing the human B1 receptor. NVP-SAA164 showed high affinity for the human B1 receptor expressed in HEK293 cells (K(i) 8 nM), and inhibited increases in intracellular calcium induced by desArg10kallidin (desArg10KD) (IC50 33 nM). While a similar high affinity was observed in monkey fibroblasts (K(i) 7.7 nM), NVP-SAA164 showed no affinity for the rat B1 receptor expressed in Cos-7 cells. In transgenic mice in which the native B1 receptor was deleted and the gene encoding the human B1 receptor was inserted (hB1 knockin, hB1-KI), hB1 receptor mRNA was induced in tissues following LPS treatment. No mRNA encoding the mouse or human B1 receptor was detected in mouse B1 receptor knockout (mB1-KO) mice following LPS treatment. Freund's complete adjuvant-induced mechanical hyperalgesia was similar in wild-type and hB(1)-KI mice, but was significantly reduced in mB1-KO animals. Mechanical hyperalgesia induced by injection of the B1 agonist desArg10KD into the contralateral paw 24 h following FCA injection was similar in wild-type and hB1-KI mice, but was absent in mB1-KO animals. Oral administration of NVP-SAA164 produced a dose-related reversal of FCA-induced mechanical hyperalgesia and desArg10KD-induced hyperalgesia in hB1-KI mice, but was inactive against inflammatory pain in wild-type mice. These data demonstrate the use of transgenic technology to investigate the in vivo efficacy of species selective agents and show that NVP-SAA164 is a novel orally active B1 receptor antagonist, providing further support for the utility of B1 receptor antagonists in inflammatory pain conditions in man.
Subject(s)
Analgesics/therapeutic use , Benzamides/therapeutic use , Bradykinin B1 Receptor Antagonists , Hyperalgesia/drug therapy , Receptor, Bradykinin B1/metabolism , Sulfonamides/therapeutic use , Administration, Oral , Analgesics/chemistry , Analgesics/pharmacology , Animals , Benzamides/chemistry , Benzamides/pharmacology , COS Cells , Cell Line , Dose-Response Relationship, Drug , Female , Gene Expression Regulation/drug effects , Gene Expression Regulation/physiology , Humans , Hyperalgesia/genetics , Hyperalgesia/metabolism , Macaca mulatta , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Rats , Receptor, Bradykinin B1/genetics , Sulfonamides/chemistry , Sulfonamides/pharmacologyABSTRACT
AIMS: To determine the utility of plain radiography for suspected upper aerodigestive tract fishbone impaction in New Zealand fish species. METHODS: Tissue densities of the least and most dense regions of the upper aerodigestive tract were measured on a lateral soft tissue X-ray of the neck. Densities of the measured regions were reproduced in two custom manufactured radiological phantoms. Epipleural bones from 22 commonly eaten New Zealand fish species were X-rayed within these phantoms. Forty-one Emergency Department doctors graded the X-ray visibility of each bone using a five point visual analogue scale. RESULTS: Twenty species (90.9%) returned a sensitivity of 95% or greater when viewed within the least dense phantom. The two species with lesser sensitivities within the least dense phantom were Red Cod (90.2%) and Ray's Bream (58.8%). Only one species (Black Cardinalfish; 4.5%) returned a sensitivity of 95% or greater when viewed within the most dense phantom. CONCLUSIONS: Bones from the majority of commonly eaten New Zealand fish species are poorly visible when X-rayed in a background of soft tissue density. Given fishbones frequently impact in regions of high tissue density, plain radiography would appear insufficiently sensitive to exclude upper aerodigestive tract fishbone impaction.